clozapine and naxagolide

Most antipsychotics are thought to have an effect on D(2) and D(3) receptors. The development of carbon 11-labeled (+)-4-propyl-9-hydroxynaphthoxazine ([(11)C]-(+)-PHNO), the first agonist radioligand with higher affinity for D(3) than D(2) receptors, allows one to differentiate the effects of antipsychotics on high-affinity vs low-affinity sites of the D(2) receptor and on D(3) vs D(2) receptor subtypes.. To examine the effects of antipsychotics (clozapine, risperidone, or olanzapine) on the high- vs high- + low-affinity sites of the D(2) and D(3) receptors by comparing the [(11)C]-(+)-PHNO and [(11)C]raclopride binding in the D(3) receptor-rich (globus pallidus and ventral striatum) and D(2) receptor-rich (caudate and putamen) regions.. Two sequential studies with different participants and appropriate controls were performed. The first compared the occupancy produced by 3 antipsychotics as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride. The second was a double-blind, placebo-controlled experiment to compare the effect of pramipexole (a D(3) receptor-preferring agonist) vs placebo on the increased [(11)C]-(+)-PHNO signal observed in the globus pallidus of patients.. Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.. Twenty-three patients with schizophrenia and 23 healthy controls.. Antipsychotic occupancies as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride.. The antipsychotic-treated patients showed high occupancies with both [(11)C]-(+)-PHNO and [(11)C]raclopride in the dorsal striatum, with [(11)C]raclopride occupancies about 20% higher. Most strikingly, patients did not show any occupancy with [(11)C]-(+)-PHNO in the globus pallidus as compared with normal controls or with their own scans using [(11)C]raclopride. This unblocked [(11)C]-(+)-PHNO signal was displaced by a single dose of pramipexole.. Antipsychotics block both the high- and low-affinity states of the D(2) receptors across the brain, but antipsychotic treatment does not block the [(11)C]-(+)-PHNO signal in the D(3) receptor-rich regions, despite the ongoing D(2) receptor blockade. This [(11)C]-(+)-PHNO signal in regions such as the globus pallidus seems increased despite antipsychotic treatment and is displaceable by a D(3) receptor-preferring agonist. The radiotracer [(11)C]-(+)-PHNO and the data open up new avenues for exploring the potential therapeutic significance of the D(3) receptor in schizophrenia.

Topics: Adult; Antipsychotic Agents; Basal Ganglia; Benzodiazepines; Benzothiazoles; Binding, Competitive; Carbon Radioisotopes; Caudate Nucleus; Clozapine; Dopamine Agonists; Dopamine Antagonists; Double-Blind Method; Female; Globus Pallidus; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Olanzapine; Oxazines; Positron-Emission Tomography; Pramipexole; Putamen; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia

The present studies were conducted to evaluate the modification of the behavioral effects of the selective D2 agonist (+)-4-propyl-9-hydroxynaphthoxazine [(+)-PHNO] by dopamine receptor blockade. In squirrel monkeys responding under a fixed-ratio schedule of stimulus-shock termination, the effects of (+)-PHNO were determined alone and in combination with the selective D2 antagonist eticlopride, the selective D1 antagonist (-)-trans-6,7,7a,8,9,13b- hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo(d)naphtho-(2,1)azepine (SCH 39166), the nonselective D1/D2 antagonist cis-flupentixol or the atypical neuroleptic clozapine. When administered alone, (+)-PHNO produced dose-dependent decreases in rates of responding. Pretreatment with eticlopride and cis-flupentixol resulted in dose-dependent right-ward shifts of the (+)-PHNO dose-effect curve, indicative of surmountable antagonism. Pretreatment with SCH 39166 and clozapine failed to antagonize the effects of (+)-PHNO and resulted in a downward shift of the (+)-PHNO dose-effect curve. Other experiments were conducted to determine the duration of either catalepsy-associated behavior or repetitive scratching produced by (+)-PHNO alone and in combination with selected dopamine receptor blockers. Low doses of (+)-PHNO (0.001-0.003 mg/kg) increased the duration of catalepsy-associated behavior, whereas higher doses (0.003-0.01 mg/kg) restored the duration of catalepsy-associated behavior to control values and produced increases in the duration of repetitive scratching.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Benzazepines; Clozapine; Dopamine Agents; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Interactions; Flupenthixol; Male; Oxazines; Receptors, Dopamine D1; Receptors, Dopamine D2; Saimiri; Salicylamides